Hydrazones

ABSTRACT

Compounds of formula I ##STR1## wherein A, X, Z and R 1  -R 5  are as defined in the description, and their salts have valuable pharmaceutical properties and are effective especially against tumours. They are prepared in a manner known per se.

This is a divisional of Ser. No. 08/346,964, filed Nov. 30, 1994, U.S.Pat. No. 5,461,076, which is a divisional of Ser. No. 08/218,854, filedMar. 28, 1994, now U.S. Pat. No. 5,395,855, which is a continuation ofSer. No. 07/939,782, filed Sep. 3, 1992, which is a continuation in partof Ser. No. 07/695,858, filed May 6, 1991, abandoned.

The invention relates to compounds of formula I ##STR2## wherein A is adirect bond or --(CH₂)_(n) --, wherein n is 1, 2 or 3; X is a radical--C(═Y)--NR₆ R₇ ; Y is NR₈, O or S; Z is NR₉, O or S; R₁ and R₂ are eachindependently of the other hydrogen or one or more substituents otherthan hydrogen: the radicals R₃, R₄, R₆, R₈ and R₉ are each independentlyof the others hydrogen or lower alkyl; and R₅ and R₇ are eachindependently of the other hydrogen, lower alkyl, hydroxy, etherified oresterfied hydroxy or unsubstituted or mono- or di-substituted amino;tautomers thereof, and salts thereof, especially certain acid additionsalts, to a process for the preparation of those compounds, topharmaceutical compositions comprising those compounds, to the use ofthose compounds for the therapeutic treatment of the human or animalbody or for the manufacture of pharmaceutical compositions.

Tautomers may occur, for example, when Z is NR₉ and R₃ and/or R₄ and/orR₅ are hydrogen:

The corresponding guanyl radical, represented by --N(R₃)--C(═Z)--NR₄ R₅in formula I, can then, for example, also be in the tautomeric form--N═C(--ZH)--NR₄ R₅, --N(R₃)--C(--ZH)═NR₅ or --N(R₃)--C(--ZH)═NR₄.

A further example: when Y is NR₈ and R₆ and/or R₇ is hydrogen, then thecorresponding amidine structure, defined as X═--C(═Y)--NR₆ R₇ in formulaI, may also be in the tautomeric form --C(--YH)═NR₇ or --C(--YH)═NR₆.The existence of those and similar tautomers is familiar to the personskilled in the art. All those tautomers are covered by the generalformula I.

In the case where A is a group --(CH₂)_(n) -- and R₂ is other thanhydrogen, the substituent(s) corresponding to the radical R₂ can also beLinked to the carbon atoms of the group --(CH₂)_(n) --.

R₂ is, for example, hydrogen or from one to four substituents other thanhydrogen, especially hydrogen or one or two substituents other thanhydrogen and more especially hydrogen or one substituent other thanhydrogen.

R₁ is, for example, hydrogen or from one to three substituents otherthan hydrogen and especially hydrogen or one or two substituents otherthan hydrogen.

The general terms used hereinabove and hereinbelow preferably have thefollowing meanings in the context of this Application:

The term "lower" denotes a radical having up to and including 7 andespecially up to and including 4 carbon atoms.

Lower alkyl is, for example, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl,preferably ethyl and especially methyl.

A substituent other than hydrogen is, for example, lower alkyl,trifluoromethyl, cycloalkyl, aryl-lower alkyl, hydroxy, lower alkoxy,aryl-lower alkoxy, aryloxy; acyloxy, for example lower alkanoyloxy;halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino; acylamino,for example lower alkanoylamino; nitro, lower alkanoyl, arylcarbonyl,carboxy, lower alkoxycarbonyl, carbamoyl (--CONH₂), N-loweralkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-arylcarbamoyl, cyano,mercapto, lower alkylthio, lower alkylsulfonyl, sulfamoyl (--SO₂ NH₂),N-lower alkylsulfamoyl or N,N-di-lower alkylsulfamoyl.

Aryl is, for example, phenyl or naphthyl, such as 1- or 2-naphthyl. Thephenyl and naphthyl radicals can be unsubstituted or substituted,especially as indicated below for phenyl. Aryl is preferably phenyl thatis unsubstituted or substituted by one or more, especially one or twosubstituents from the group consisting of lower alkyl, lower alkoxy,hydroxy, lower alkanoyloxy, nitro, amino, halogen, trifluoromethyl,carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl, cyano, lower alkanoyl, arylcarbonyl, loweralkylsulfonyl, sulfamoyl, N-lower alkyl-sulfamoyl and N,N-di-loweralkylsulfamoyl. Aryl is especially phenyl that is unsubstituted orsubstituted by lower alkyl, lower alkoxy, hydroxy, halogen or bytrifluoromethyl, and is more especially phenyl.

Arylcarbonyl is, for example, benzoyl that is unsubstituted orsubstituted by lower alkyl, lower alkoxy, hydroxy, halogen or bytrifluoromethyl, and is especially benzoyl.

Aryl-lower alkyl is, for example, phenyl-lower alkyl and especiallybenzyl.

Halogen is especially chlorine and bromine, but may also be fluorine oriodine.

Lower alkanoyl is, for example, formyl, acetyl, propionyl or pivaloyl.

Cycloalkyl is preferably C₃ -C₈ - and especially C₅ -C₆ cycloalkyl,which is intended to indicate that it contains from 3 to 8 and 5 or 6ring carbon atoms, respectively. It may, however, also be substituted,for example by lower alkyl.

Etherified hydroxy is, for example, lower alkoxy. Esterified hydroxy is,for example, lower alkanoyloxy. Monosubstituted amino is, for example,lower alkylamino. Di-substituted amino is, for example, di-loweralkylamino, lower alkyleneamino, for example C₄ -C₇ - and especially C₄-C₅ -alkyleneamino, for example piperidino, or oxa-, thia- or aza-loweralkyleneamino, for example morpholino, thiomorpholino, piperazino or4-lower alkylpiperazino.

Salts of compounds according to the invention are especiallypharmaceutically acceptable, non-toxic salts. For example, compounds offormula I having basic groups may form acid addition salts, for examplewith inorganic acids, such as hydrochloric acid, sulfuric acid orphosphoric acid, or with suitable organic carboxylic or sulfonic acids,for example acetic acid, fumaric acid or methanesulfonic acid, or, forexample, with amino acids, such as arginine or lysine. When severalbasic groups are present, mono- or poly-salts may be formed. Compoundsof formula I having an acidic group, for example carboxy, and a basicgroup, for example amino, may be, for example, in the form of internalsalts, that is to say in zwitterionic form, or part of the molecule maybe in the form of an internal salt and another pan may be in the form ofa normal salt.

The aim of the present invention is also to provide novel acid additionsalts of pharmacologically acceptable compounds, which salts have a goodsolubility in physiological liquids and/or liquids that are similar tophysiological liquids, such as physiological saline solution, mannitolsolution or phosphate buffers, and/or good absorbability in the case ofenteral, such as oral, administration, for example by the formation ofion pairs, such as lipophilic ion pairs.

The acid addition salts according to the invention of bases of formula Iare comprising those with an acid [PA] that is a mono-or poly-proticacid selected from carbonic acid, alkanoic acids that are unsubstitutedor mono- or poly-substituted, with the exception of formic acid,unsubstituted acetic acid, lysine and arginine; alkenoic acids that areunsubstituted or substituted, with the exception of unsubstitutedfumaric acid; cycloalkyl-carboxylic acids, arylcarboxylic acids,aryl-lower alkylcarboxylic acids, wherein lower alkyl is unsubstitutedor substituted, aryl-lower alkenylcarboxylic acids,heterocyclyl-carboxylic acids, alkanesulfonic acids that areunsubstituted or substituted, with the exception of unsubstitutedmethanesulfonic acid; aromatic sulfonic acids, alkylsulfuric acids,N-substituted sulfamic acids, organic acids without carboxy, sulfo,sulfate or phospho groups, and also selected from pyrophosphoric acidand hydriodic acid, and tautomers thereof.

The invention also relates to to processes for the preparation of thoseacid addition salts, to pharmaceutical compositions comprising thoseacid addition salts, and to the use of those acid addition salts in thetherapeutic treatment of the human or animal body or in the preparationof pharmaceutical compositions.

The following definitions relate to the acids [PA] ([PA] stands for"Protic Acid"):

Alkanoic acids are especially C₁ -C₂₀ alkanoic acids with the exceptionof formic acid and unsubstituted acetic acid, preferably C₂ -C₇ alkanoicacids, such as propionic acid, butyric acid, isobutyric acid, pentanoicacid, hexanoic acid or heptanoic acid, or also octanoic acid, decanoicacid or dodecanoic acid, especially propionic acid or octanoic acid, allof those alkanoic acids being unsubstituted or substituted one or moretimes, especially from one to six times, preferably by hydroxy, eitheronce, such as in glycolic acid, lactic acid or 2-hydroxybutyric acid, orseveral times, for example up to five times, such as in gluconic acid orglucose monocarboxylic acid ("glucoheptonic acid"), by carboxy, forexample in C₂ -C₂₀ alkanoic di-acids, especially C₂ -C₇ alkanoicdi-acids, such as in succinic acid, or also adipic acid, pimelic acid,suberic acid or azelaic acid, by hydroxy and carboxy, such as in malicacid, tartaric acid, citric acid, glucaric acid or galactaric acid, byamino or amino and carboxy and/or by one or two radicals selectedindependently from mercapto, methylmercapto, hydroxy, phenyl,4-hydroxyphenyl, naphthyl, cyclohexyl, imidazolyl and indolyl, such asin amino acids, lysine and arginine being excluded, especially glutamicacid or aspattic acid in the (D)-, (L)- or (D,L)-form, preferably the(D)- or (L)-form, by substituted amino or substituted amino and carboxyand/or by one or two radicals selected independently from mercapto (alsoin oxidised form as the corresponding disulfide consisting of twomolecules of the corresponding mercaptan), methylmercapto, hydroxy,phenyl, 4-hydroxyphenyl, naphthyl, cyclohexyl, imidazolyl and indolyl,such as in amino acids, for example in N-mono- or N,N-di-loweralkylamino acids, such as N-methyl-glycine, or in N-lower alkanoylaminoacids, such as acetylaminoacetic acid (N-acetyl-glycine),N-acetylasparagine or N-acetylcystine, by oxo, such as in pyruvic acidor aceto-acetic acid, by phospho and amino, such as in phosphoserine, orby phospho and hydroxy, such as in 2- or 3-glycerophosphoric acid,glucose-6-phosphoric acid, glucose-1-phosphoric acid orfructose-1,6-hisphosphoric acid. Amino acids are especially α-aminoacids which may be in the (D)-, (L)- or (D,L)-form, preferably the (L)-or (D)-form, and, when other centres of asymmetry are present, they mayalso be in the form of other isomers, for example selected from glycine(H--Gly--OH), alaninc (H--Ala--OH), valine (H--Val--OH), norvaline(α-aminovaleric acid), leucine (H--Leu--OH), isoleucine (H--Ile--OH),norleucine (α-aminohexanoic acid, H--Nle--OH), serine (H--Ser--OH),homoserine (α-amino-γ-hydroxy-butyric acid), threonine (H--Thr--OH),methionine (H--Met--OH), cysteine (H--Cys--OH) (which may also bepresent in oxidised form as cystine), phenylalanine (H--Phe--OH),tyrosine (H--Tyr--OH), β-phenylserine (β-hydroxyphenylalanine),phenylglycine, α-naphthylalanine (H--Nal--OH), cyclohexylalanine(H--Cha--OH), cyclohexylglycine, tryptophan (H--Trp--OH), aspattic acid(H--Asp--OH), asparagine (H--Asn--OH), amino-malonic acid, glutamic acid(H--Glu--OH), glutamine (H--Gln--OH), histidine (H--HisOH),δ-hydroxylysine, ornithine (α,δ-diaminovaleric acid), α,γ-diaminobutyricacid and α, β-diaminopropionic acid, and, unless otherwise indicated,from arginine (H--Arg--OH) and lysine (H--Lys--OH). Especially preferredamino acids are glycine, serine, cystine, aspanic acid and glumtalcacid, especially aspanic acid and gtutamic acid. Amino acids may also beomitted from the definition of substituted alkanoic acids.

Alkenoic acids are, for example, C₂ -C₁₀ alkenoic di-acids that areunsubstituted, such as maleic acid, or substituted, preferably byhydroxy, such as in hydroxymaleic acid (tautomen oxalacetic acid), orlower alkyl, for example methyl, such as in methylmaleic acid.Unsubstituted fumaric acid is excluded.

Cycloalkylcarboxylic acids are preferably C₄ -C₁₂ cycloalkylcarboxylicacids wherein the cycloalkyl radical is mono-, bi- or tri-cyclic,preferably monocyclic or tricyclic, for example cyclopentyl, cyclohexyl,cycloheptyl or adamantyl, and is, for example, unsubstituted, such as incyclohexanecarboxylic acid or adamantanecarboxylic acid.

In arylcarboxylic acids, the aryl radical has, for example, from 6 to20, preferably from 6 to 14, carbon atoms, and is selected, for example,from phenyl, 1- or 2-naphthyl and indane, and is unsubstituted, such asin benzoic acid, or substituted, preferably by from 1 to 3 radicalsselected independently from lower alkyl, such as methyl, halogen, suchas fluorine, chlorine or bromine, hydroxy, lower alkoxy, for examplemethoxy, phenoxy, lower alkanoyloxy, such as acetoxy, amino and carboxy,such as in salicylic acid, 1- or 3-hydroxynaphthyl-2-carboxylic acid,3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoicacid, 4-aminosalicylic acid or phthalic acid.

In aryl-lower alkylcarboxylic acids, aryl is as last defined forarylcarboxylic acids and is unsubstituted or substituted as definedthere, and lower alkyl is preferably methyl or ethyl, lower alkyl beingunsubstituted, such as in phenylacetic acid, or substituted, for exampleby hydroxy, such as in mandelic acid.

In aryl-lower alkenylcarboxylic acids, aryl is as last defined forarylcarboxylic acids, and lower alkenyl has preferably from 2 to 4carbon atoms, such as in cinnamic acid.

Heterocyclylcarboxylic acids contain, for example, heterocyclylcomprising from one to three rings, preferably one or two rings, that issaturated or partially or completely unsaturated, preferably saturatedor unsaturated, and has from 5 to 12 ring atoms, preferably from 5 to 7ring atoms, which are selected from carbon and up to three hetero atoms,preferably one or two hetero atoms being present, especially oxygen,nitrogen and/or sulfur, especially oxygen and nitrogen, heterocyclylbeing, for example, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl ora completely or partially saturated derivative of those radicals, orpyranyl or furanyl, and being unsubstituted, such as in nicotinic acidor isonicotinic acid, or from mono- to penta-substituted, preferably byhydroxy and/or by hydroxy-lower alkyl, for example hydroxy orhydroxymethyl, such as in glucuronic acid or galacturonic acid.

Alkanesulfonic acids are especially C₂ -C₂₀ alkanesulfonic acids,preferably C₂ -C₇ alkyl-sulfonic acids, such as ethanesulfonic acid,that are unsubstituted or substituted, preferably by one or two radicalsselected from hydroxy and sulfo, such as in 2-hydroxyethane-sulfonicacid, or alkanedisulfonic acids, for example lower alkanedisulfonicacids, such as ethane-1,2-disulfonic acid. Methanesulfonic acid isexcluded.

In aromatic sulfonic acids, the aromatic residue is, for example, arylas defined for aryl-carboxylic acids and is unsubstituted, such as inbenzenesulfonic acid or 2-naphthalene-sulfonic acid, or is substitutedas in arylcarboxylic acids, especially by lower alkyl, for examplemethyl, such as in 2-, 3- or 4-methylbenzenesulfonic acid, or by afurther sulfonyl radical, such as in 1,3-benzenesulfonic acid ornaphthalene-1,5-disulfonic acid, such as, especially, in1,5-naphthalenedisulfonic acid.

Alkylsulfuric acids are especially C₁ -C₂₀ alkylsulfuric acids,especially lower alkylsulfuric acids, such as methylsulfuric acid orethylsulfuric acid, or dodecylsulfuric acid.

N-substituted sulfamic acids are, for example, N-cycloalkylsulfamicacids, wherein cyclo-alkyl is preferably C₄ -C₁₂ cycloalkyl and thecycloalkyl radical is mono-, bi- or tri-cyclic, for example cyclopentyl,cyclohexyl, cycloheptyl or adamantyl, preferably monocyclic, such as inN-cyclohexylsulfamic acid, or N-alkylsulfamic acids, preferably N-loweralkyl-sulfamic acid, such as methyl-, ethyl- or propyl-sulfamic acid.

Organic acids without carboxy, sulfo, sulfate or phospho groups contain,for example, acidic hydroxy groups, such as in ascorbic acid.

Important acids are carbonic acid, propionic acid, octanoic acid,decanoic acid, dodecanoic acid, glycolic acid, lactic acid,2-hydroxybutyric acid, gluconic acid, glucose monocarboxylic acid,succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,malic acid, tartaric acid, clinic acid, glucaric acid, galactaric acid,glutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid,N-acetylasparagine, N-acetylcystine, pyruvic acid, acetoacetic acid,phosphoserine, 2- or 3-glycerophosphoric acid, glucose-6-phosphoricacid, glucose-1-phosphoric acid, fructose-1,6-bisphosphoric acid, maleicacid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid,adamantane-carboxylic acid, benzoic acid, salicylic acid, 1- or3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid,2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-amino-salicylic acid,phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid,nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid,ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid,ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonicacid, 1,5-naphthalenedisulfonic acid, 2-, 3- or 4-methylbenzenesulfonicacid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid,N-cyclohexylsulfamic acid, methyl-, ethyl- or propyl-sulfamic acid, orascorbic acid.

Very important acids are octanoic acid, succinic acid, adipic acid,salicylic acid, benzene-sulfonic acid, 1,5-naphthalenesulfonic acid orN-cyclohexylsulfamic acid, very especially salicylic acid or, moreespecially, adipic acid or benzenesulfonic acid.

Very important acids are equally tartaric acid, especially L-tartaricacid, lactic acid or citric acid.

The mentioned acids, especially if they contain several acidic groups ofdiffering acidity that can dissociate protons, may also be in the formof mixed salts with carbons, for example alkali metal cations, such assodium or potassium ions, alkali metal salts, such as magnesium salts,or zinc salts, the acid component before the reaction yielding thementioned mixed salts containing at least one other dissociable proton,or they may be present in the resulting salts in a form in which not allprotons are freed, but at least one proton has been transferred to therelevant base of formula I. For example, carbonic acid can be used inthe form of a hydrogen carbonate salt, such as sodium or potassiumhydrogen carbonate.

The acid addition salts of a base of formula I with an acid [PA] mayalso be in the form of hydrates. Crystals may also include othersolvents used for crystallisation.

For the purposes of isolation or purification it is also possible to usepharmaceutically unacceptable salts, for example pierates orperchlorates. Only the pharmaceutically acceptable, non-toxic salts areused therapeutically and these are therefore preferred.

Depending on the structural configuration, the compounds of formula Iand their salts, especially their acid addition salts, for example, withacids [PA], of the present invention may be in the form of isomericmixtures or in the form of pure isomers. If, for example, R₂ is asubstituent other than hydrogen, the corresponding compound of formula Ior the acid addition salts of compounds of formula I may be in the formof racemates or racemic salts or of enantiomers or enantiomerically puresalts or, especially in the case of a salt with an acid [PA], also inthe form of diastereoisomeric salts, for example in the presence ofacids having centres of asymmetry, such as the mentioned amino acids,lactic acid or tartaric acid.

The compounds according to the invention, especially their acid additionsalts, have valuable, especially pharmacologically acceptable,properties. In particular, they have a strong, specific inhibitoryaction on the enzyme S-adenosylmethionine decarboxylase (SAMDC). SAMDCas a key enzyme plays an important part in the polyamine synthesis thattakes place in virtually all cells of mammals, including humans. Thepolyamine concentration in the cell is regulated by SAMDC. Inhibition ofthe SAMDC enzyme results in a reduction in the polyamine concentration.Since a reduction in the polyamine concentration effects inhibition ofcell growth, it is possible by administering SAMDC-inhibiting substancesto inhibit the growth of both eukaryotic and prokaryotic cells and evento kill cells or to inhibit the onset of cell differentiation.

The inhibition of the SAMDC enzyme can be demonstrated, for example,using the method of H. G. Williams-Ashmann and A. Schenone, Biochem.Biophys. Res. Communs. 46, 288 (1972). The compounds of the inventionhave IC₅₀ values of a minimum of approximately 0.005 μM.

A further advantage of the compounds according to the invention lies inthe fact that in comparison with their strong inhibitory action on SAMDCtheir inhibitory action on diamine oxidase is only slight and they arewell tolerated. According to J. Jaenne and D. R. Morris, Biochem. J.218,974 (1984), the inhibition of diamine oxidase is disadvantageoussince it can result in an accumulation of putrescine and indirect SAMDCactivation.

The compounds of formula I are therefore, for example, useful for thetreatment of benign and malignant tumours. They can bring about theregression of tumours and also prevent the spread of rumour cells andthe growth of micrometastases. Furthermore, they can be used, forexample, for the treatment of protozoa infections, for exampletrypanosomiasis, malaria, or pulmonary, inflammation caused byPneumocystis carinii.

As selective SAMDC-inhibitors, the compounds of formula I, or especiallytheir acid addition salts, can be used alone or alternatively incombination with other pharmacologically active substances. Possiblecombinations are, for example, a combination with (a) inhibitors ofother enzymes of the polyamine biosynthesis. for example ornithinedecarboxylase inhibitors, (b) inhibitors of protein kinase C, (c)inhibitors of tyrosine protein kinase, (d) cytokines, (e) negativegrowth regulators, (f) aromarase inhibitors, (g) anti-oestrogens or (h)classic cytostatic active ingredients.

The invention relates preferably to compounds of formula I wherein A isa direct bond or --(CH₂)_(n) --, wherein n is 1 or 2; X is a radical--C(═Y)--NR₆ R₇ ; Y is NR₈, O or S; Z is NR₉, O or S; R₁ and R₂ are eachindependently of the other hydrogen or one or two substituents from thegroup consisting of lower alkyl, trifluoromethyl, cycloalkyl, aryl-loweralkyl, hydroxy, lower alkoxy, aryl-lower alkoxy, aryloxy, loweralkanoyloxy, halogen, amino, N-lower alkylamino, N,N-di-loweralkylamino, lower alkanoylamino, nitro, lower alkanoyl, arylcarbonyl,carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl,N,N-di-lower alkylcarbamoyl, N-arylcarbamoyl, cyano, mercapto, loweralkylthio, lower alkylsulfonyl, sulfamoyl, N-lower alkylsulfamoyl andN,N-di-lower alkyl-sulfamoyl, aryl being phenyl that is unsubstituted orsubstituted by lower alkyl, lower alkoxy, hydroxy, halogen or bytrifluoromethyl; the radicals R₃, R₄, R₆, R₈ and R₉ are eachindependently of the others hydrogen or lower alkyl; and R₅ and R₇ areeach independently of the other hydrogen, lower alkyl, hydroxy, loweralkoxy, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino,lower alkyleneamino or oxa-, thia- or aza-lower alkyleneamino; tautomersthereof, and salts thereof.

Preference is given especially to compounds of formula I wherein A is adirect bond or --(CH₂)_(n) --, wherein n is 1 or 2; X is a radical--C(═Y)--NR₆ R₇ ; Y is NH, O or S; Z is NH, O or S; R₁ and R₂ are eachindependently of the other hydrogen or one or two substituents from thegroup consisting of lower alkyl, trifluoromethyl, phenyl-lower alkyl,hydroxy, lower alkoxy and halogen; the radicals R₃, R₄ and R₆ arehydrogen; and R₅ and R₇ are each independently of the other hydrogen,lower alkyl, hydroxy or amino; tautomers thereof, and salts thereof.

Preference is given more especially to compounds of formula I wherein Ais a direct bond or --CH₂ --; X is a radical --C(═Y)--NR₆ R₇ ; Y is NHor S; Z is NH: R₁ is hydrogen or one or two substituents from the groupconsisting of lower alkyl, hydroxy, lower alkoxy and halogen; R₂ ishydrogen or lower alkyl; the radicals R₃, R₄ and R₆ are hydrogen; and R₅and R₇ are each independently of the other hydrogen, lower alkyl orhydroxy: tautomers thereof, and pharmaceutically acceptable saltsthereof.

Very special preference is given to compounds of formula I wherein A isa direct bond, X is a radical --C(═NH)--NH₂ ; Z is NH: R₁ is hydrogen orone or two substituents from the group consisting of lower alkyl,hydroxy and lower alkoxy; the radicals R₂, R₃ and R₄ are hydrogen; andR₅ is hydrogen or hydroxy; tautomers thereof, and pharmaceuticallyacceptable salts thereof.

Special mention should be made of each of the following sub-groups of agroup of compounds of formula I:

(a) compounds of formula I wherein A is a direct bond; (b) compounds offormula I wherein X is a radical --C(═NH)--NH₂ ; (c) compounds offormula I wherein Z is NH, R₄ is hydrogen and R₅ is hydrogen or hydroxy;and (d) compounds of formula I wherein R₁ and R₂ are hydrogen.

The invention relates especially to the specific compounds described inthe Examples and salts thereof.

With special regard to the acid addition salts of bases of formula I,the invention relates preferably to me acid addition salts of a base offormula I wherein A is a direct bond or --(CH₂)_(n) --, n being 1 or 2;X is a radical --C(═Y)--NR₆ R₇ ; Y is NR₈, O or S; Z is NR₉, O or S;each of R₁ and R₂, independently of the other, is hydrogen or one or twosubstituents selected from the group consisting of lower alkyl,trifluoromethyl, cycloalkyl, aryl-lower alkyl, hydroxy, lower alkoxy,aryl-lower alkoxy, aryloxy, lower alkanoyloxy, halogen, amino, N-loweralkylamino, N,N-di-lower alkylamino, lower alkanoylamino, nitro, loweralkanoyl, arylcarbonyl, carboxy, lower alkoxycarbonyl, carbamoyl,N-lower alkyl-carbamoyl, N,N-di-lower alkylcarbamoyl, N-arylcarbamoyl,cyano, mercapto, lower alkylthio, lower alkylsulfonyl, sulfamoyl,N-lower alkylsulfamoyl and N,N-di-lower alkyl-sulfamoyl, aryl beingphenyl that is unsubstituted or substituted by lower alkyl, loweralkoxy, hydroxy, halogen or by trifluoromethyl; each of the radicals R₃,R₄, R₆, R₈ and R9, independently of the others, is hydrogen or loweralkyl; and each of R₅ and R₇, independently of the other, is hydrogen,lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, amino, loweralkylamino, di-lower alkylamino, lower alkyleneamino or oxa-, thia- oraza-lower alkyleneamino;

with an acid [PA] that is a mono- or poly-protic acid selected fromcarbonic acid, alkanoic acids that are unsubstituted or mono- orpoly-substituted, with the exception of formic acid, unsubstitutedacetic acid, lysine and arginine: alkenoic acids that are unsubstitutedor substituted, with the exception of fumaric acid; cycloalkylcarboxylicacids, arylcarboxylic acids, aryl-lower alkylcarboxylic acids, whereinlower alkyl is unsubstituted or substituted, aryl-loweralkenylcarboxylic acids, heterocyclylcarboxylic acids, alkanesulfonicacids that are unsubstituted or substituted, with the exception ofmethanesulfonic acid; arylsulfonic acids, alkylsulfuric acids,N-substituted sulfamic acids, organic acids without carboxy, sulfo,sulfate or phospho groups, and also selected from pyrophosphoric acidand hydriodic acid, for example one of the acids defined above as beingimportant, for example one of the acids defined as being very,important,

or tautomers thereof.

Especially preferred are the acid addition salts of a base of formula Iwherein A is a direct bond or --(CH₂)_(n) --, wherein n is 1 or 2; X isa radical --C(═Y)--NR₆ R₇ ; Y is NH, O or S; Z is NH, O or S; each of R₁and R₂, independently of the other, is hydrogen or one or twosubstituents selected from the group consisting of lower alkyl,trifluoromethyl, phenyl-lower alkyl, hydroxy, lower alkoxy and halogen;the radicals R₃, R₄ and R₆ are hydrogen; and each of R₅ and R₇,independently of the other, is hydrogen, lower alkyl, hydroxy or amino:with an acid [PA] that is a mono- or poly-protic acid selected fromcarbonic acid, alkanoic acids that are unsubstituted or mono- orpoly-substituted, with the exception of formic acid, unsubstitutedacetic acid, lysine and arginine; alkenoic acids that are unsubstitutedor substituted, with the exception of fumaric acid; cycloalkylcarboxylicacids, arylcarboxylic acids, aryl-lower alkylcarboxylic acids, whereinlower alkyl is unsubstituted or substituted, aryl-loweralkenylcarboxylic acids, heterocyclylcarboxylic acids, alkanesulfonicacids that are unsubstituted or substituted, with the exception ofmethane-sulfonic acid: aromatic sulfonic acids, alkylsulfuric acids,N-substituted sulfamic acids, organic acids without carboxy, sulfo,sulfate or phospho groups, and also selected from pyrophosphoric acidand hydriodic acid, for example one of the acids defined above as beingimportant, for example one of the acids defined as being very important;

or tautomers thereof.

More especially preferred are the acid addition salts of a base offormula I wherein A is a direct bond or --CH₂ --; X is a radical--C(═Y)--NR₆ R₇ ; Y is NH or S; Z is NH; R₁ is hydrogen or one or twosubstituents selected from the group consisting of lower alkyl, hydroxy,lower alkoxy and halogen: R₂ is hydrogen or lower alkyl; the radicalsR₃, R₄ and R₆ are hydrogen; and each of R₅ and R₇, independently of theother, is hydrogen, lower alkyl or hydroxy: with an acid [PA] that is asdefined above, for example one of the acids defined above as beingimportant, for example one of the acids defined as being very important:or tautomers thereof.

Most especially preferred are the acid addition salts of bases offormula I wherein A is a direct bond: X is a radical --C(═NH)--NH₂ ; Zis NH; R₁ is hydrogen or one or two substituents selected from the groupconsisting of lower alkyl, hydroxy and lower alkoxy; the radicals R₂, R₃and R₄ are hydrogen: and R₅ is hydrogen or hydroxy; with an acid [PA]that is as defined above, for example one of the acids defined above asbeing important, especially one of the acids defined as being veryimportant: or tautomers thereof.

As sub-groups of a group of acid addition salts of bases of formula Iwith acids [PA], attention is drawn to:

(a) acid addition salts of bases of formula I wherein A is a directbond: (b) acid addition salts of bases of formula I wherein X is aradical --C(═NH)--NH₂ ; (c) acid addition salts of bases of formula Iwherein Z is NH, R₄ is hydrogen, and R₅ is hydrogen or hydroxy; and (d)acid addition salts of bases of formula I wherein R₁ and R₂ arehydrogen; each of the other radicals being as defined; with acids [PA]selected from one of the groupings mentioned above, for example from theacids defined above as being very important; or tautomers thereof.

The invention relates more especially to the acid addition salts ofbases of formula I wherein A is a direct bond: X is a radical--C(═NH)--NH₂ ; Z is NH; and each of R₁, R₂, R₃, R₄ and R₅ is hydrogen:and [PA] is selected from the above-mentioned acids, or is preferablyone of the acids defined above as being important, for example one ofthe acids defined as being very important, for example an acid selectedfrom N-cyclohexylsulfamic acid, octanoic acid, salicylic acid andbenzenesulfonic acid, such as salicylic acid.

The invention relates more especially also to the acid addition salts ofbases of formula I wherein A is a direct bond: X is a radical--C(═NH)--NH₂ ; Z is NH; and each of R₁, R₂, R₃, R₄ and R₅ is hydrogen;and [PA] is preferably one of the acids defined above as being veryimportant, especially selected from tartaric acid, more especiallyL-tartaric acid, lactic acid and citric acid.

Most strongly preferred are the acid addition salts of bases of formulaI mentioned in the Examples with an acid [PA].

The compounds of formula I can be prepared, for example by

(a) condensing a compound of formula II ##STR3##

wherein the group CW₁ W₂ is carbonyl, functionally modified carbonyl orprotected carbonyl and A, X, R₁ and R₂ are as defined for formula I, ora salt thereof, if salt-forming groups are present, with an amine offormula III ##STR4##

wherein Z, R₃, R₄ and R₅ are as defined for formula I, or a saltthereof, or

(b) in a compound of formula IV ##STR5## wherein W₃ is a radical thatcan be converted into a group X in formula I and A, Z, R₁, R₂, R₃, R₄and R₅ are as defined for formula I, or a salt thereof, convening theradical W₃ into the group X; and, if desired, converting a resultingcompound of formula I into a different compound of formula I and/or, ifdesired, converting a resulting salt into the free compound or into adifferent salt and/or, if desired, converting a resulting free compoundof formula I having salt-forming properties into a salt.

In the following, more detailed description of processes a)-b), thesymbols A, X, Y, Z and R₁ -R₉ are each as defined for formula I, unlessotherwise indicated.

Process (a):

Examples of functionally modified or protected carbonyl CW₁ W₂ that maybe mentioned are: di-lower alkoxymethyl, C₁ --C₂ alkylenedioxymethyl,dihalomethyl, di-lower alkyl-thiomethyl or C₁ -C₂ alkylenedithiomethyl.

The group CW₁ W₂ in compounds of formula II is preferably in the form offree carbonyl.

The condensation reaction according to process (a) is carried out underconditions known per se for the formation of hydrazones. It ispreferably acid-catalysed. In compounds of formula II, suitableprotected carbonyl groups CW₁ W₂ are those which are converted into freecarbonyl under the conditions of the condensation.

For the preparation of compounds of formula I wherein R₅ is amino it isadvisable to use the compound of formula III in excess.

The intermediates of formula II wherein Y in the radical X is NH areobtained, for example, by first convening a compound of formula V##STR6## by treatment with hydrogen sulfide into the correspondingthiocarboxamide [--C(═S)--NH₂ ]. The latter can also be obtained by adifferent method starting from the analogous carboxamide [--C(═O)--NH₂], for example by reaction with the Lawesson reagent[2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane].The thiocarboxamides are S-alkylated, for example with lower alkyliodide or tri-lower alkyloxonium tetrafluoroborate, and thus convertedinto imino-lower alkylthio ester hydroiodides [--C(═NH)--S--alkyl . HI]or tetrafluoroborates, respectively, which can readily be converted byreaction with ammonia or amines of the formula NHR₆ R₇ into the desiredcarboximide amides of formula II [see S. Patai (Ed.), The Chemistry ofAmidines and Imidates, Wiley, London etc. 1975, p 303-304].

The preparation of the carboxamides of formula II from the cyanocompounds of formula V proceeds analogously to the preparation ofcarboxamides of formula I from cyano compounds of formula IV describedbelow under process (b) and is described in detail there.

In a further possible method of preparing compounds of formula II, acompound of formula V, wherein the group CW₁ W₂ is as defined forformula II, is treated, for example, with ethanol and hydrochloric acidin, for example, chloroform or diethyl ether, to form the correspondingiminoethyl ester hydrochloride which can be converted, for example byreaction with ammonia or a primary, or secondary, amine of the formulaNHR₆ R₇ and, for example, methanol, into the desired carboximide amideof formula 1I. In some cases, however, this method may not work as aresult of sterical hindrance by the groups A and R₁.

The starting compounds of formula V are known per se or are preparedanalogously to the known compounds.

The compounds of formula V can be prepared, for example, byintramolecular Friedel-Crafts acylation of ω-phenyl-lower alkanoic acidsof formula VI ##STR7## wherein W₄ is cyano or a cyano precursor, or acidderivatives thereof, for example acid chlorides or acid art hydrides. Inthe case of free acids, the catalyst used may be, for example,polyphosphoric acid, and in the case of acid chlorides or anhydrides thecatalyst may be, for example, AlCl₃.

In this reaction it is preferable to use compounds of formula VI whereinW₄ is not cyano but a cyano precursor, for example halogen, especiallybromine, or protected amino, for example acetylamino. After thecyclisation step, the cyano precursors can then be converted into cyanofor example in the case of bromine by reaction with copper(I) cyanide orin the case of acetylamino by removal of the acetyl protecting group,diazotisation and reaction with copper(I) cyanide.

Compounds of formula V wherein the group CW₁ W₂ is carbonyl can also beprepared, for example, by oxidation, for example with chromium trioxide(CrO₃), from the corresponding non-carbonyl compounds of formula VII##STR8## wherein W₄ is cyano or a cyano precursor as defined above. If acyano precursor is used, it should again be converted into cyano afterthe oxidation is complete, for example as indicated above.

In a further possible method of preparing the compounds of formula Vwherein the group CW₁ W₂ is carbonyl, compounds of formula II wherein Xis hydrogen are used as starting materials and the cyano group isintroduced, for example, by using a reaction sequence analogous to thatin U.S. Pat. No. 3 956 363, Example 10, which consists of nitration,reduction of the nitro group to amino, diazotisation and reaction withcopper(I) cyanide (Sandmeyer reaction).

The preparation of aminoguanidines, ammoureas and aminothioureas offormula III is known per se. Amino(thio)ureas [=semi(thio)carbazides]areprepared, for example, in an analogous manner to corresponding simple(thio-)ureas. For example, instead of an amine the correspondinghydrazine of the formula H₂ N--NHR₃ is used and is reacted, for example,with an isocyanate of the formula R₄ N═C═O or R₅ N═C═O, anisothiocyanate of the formula R₄ N═C═S or R₅ N═C═S, a carbamoyl chlorideof the formula R₄ R₅ N--COCl or a thiocarbamoyl chloride of the formulaR₄ R₅ N--CSCl. Furthermore, it is also possible, for example, to react ahydrazine of the formula H₂ N--NHR₃ with an acylisothiocyanate, forexample acetylisothiocyanate, followed by acid hydrolysis.

Aminoguanidines of formula III wherein Z is NR₉ and R₃, R₄, R₅ and R₉are as defined for formula I, are known per se and can be prepared, forexample, from corresponding aminothioureas of formula III by convertingthe latter by alkylation, for example with an alkyl tosylate or halide,into the corresponding S-alkylisothiouronium salts which are thenreacted with an amine of the formula NHR₄ R₅.

Process (b)

In the intermediates of formula IV, W₃ is, for example, free orfunctionally modified carboxy, especially halocarbonyl, cyano,imino-lower alkoxycarbonyl or imino-lower alkylthiocarbonyl, or alsothiocarbamoyl.

For the preparation of amidines of formula I (Y=NR₈) the group W₃ in acompound of formula IV can be, for example: an acid addition salt of animino-lower alkyl ester (=imino-lower alkyl ether) or imino-loweralkylthio ester, for example --C(═NH)--OC₂ H5. HCl or --C(═NH)--SC₂H₅.HI, or cyano.

The reaction of an imino-lower alkyI ester of formula IV (in salt form)with ammonia or primary or secondary amines results in the unsubstitutedor mono- or di-substituted amidines of formula I. Cyano compounds offormula IV can be converted, for example by reaction with an alkalimetal amide, for example KNH₂, or by reaction with a primary orsecondary (di-)lower alkylammonium halide, for example .sup.⊕ NH₃ CH₃Cl.sup.⊖, into an unsubstituted or mono- or di-substituted amidine offormula I.

For the preparation of carbamoyl compounds of formula I (Y=O) the groupW₃ in a compound of formula IV may be, for example: carboxy,halocarbonyl (for example --COCl), lower alkoxycarbonyl or cyano. Theformation of unsubstituted or mono- or di-substituted carbamoylcompounds of formula I from corresponding intermediates of formula IVwherein W₃ is carboxy, halocarbonyl or lower alkoxycarbonyl, by reactionwith ammonia or primary or secondary amines is known per se.Intermediates of formula IV wherein W₃ is cyano can be converted, forexample by partial hydrolysis, in the manner of a Graf-Ritter reaction,or by way of carboxylic acid ester imide salts, into unsubstituted ormono- or di-substituted carbamoyl compounds of formula I. The conditionsfor the hydrolysis of the cyano intermediates can be so chosen that thereaction is interrupted at the amide stage. Especially suitable for thispurpose is hydrolysis with acids, for example with 80% sulfuric acid(with heating), polyphosphoric acid (at 110°-150° C.), hydrogenbromide/glacial acetic acid (at room temperature, in the presence offormic acid or without a further solvent) or HCl gas in etherealsolution followed by the addition of water or aqueous hydrochloric acid,or reaction with boron halides.

Using the Graf-Ritter reaction it is also possible to prepareN-substituted amides from nitriles of formula IV. For this purpose thenitriles are reacted in the presence of a strong acid, especially 85-90%sulfuric acid, or alternatively polyphosphoric acid, formic acid, borontrifluoride or other Lewis acids, but not aluminium chloride, withcompounds capable of forming carbenium ions in the acidic medium, thatis to say, for example, with olefins, such as propylene, or alcohols,such as ethanol.

The carboxylic acid ester imides are obtained, for example, byacid-catalysed addition of alcohols to the nitriles of formula IV. Theamides are obtained from the ester imides in the manner of a Pinnercleavage by thermal decomposition of the ester imide salts attemperatures above approximately 80° C.

Compounds of formula IV wherein W₃ is cyano can be prepared, forexample, by reacting a compound of formula V with a compound of formulaIII in accordance with process a). From compounds of formula IV whereinW₃ is cyano it is possible to prepare, in a manner known per se or asdescribed above, the other compounds of formula IV wherein W₃ is freecarboxy or carboxy functionally modified in some other way.

Compounds of formula I wherein X is a radical --C(═NH)--NR₆ R₇ can alsobe obtained by reacting compounds of formula IV wherein W₃ is a radical--C(═S)--NH₂, with S-alkylation, for example with tri-lower alkyloxoniumtetrafluoroborate, and by subsequent reaction with ammonia or an amineof the formula NHR₆ R₇ or a corresponding ammonium salt, for example thechloride.

Compounds of formula I can be converted into different compounds offormula I.

For example, compounds of formula I wherein X is a radical --C(═S)--NH₂can be converted by S-alkylation, for example with tri-loweralkyloxonium tetrafluoroborate, and subsequent reaction with ammonia oran amine of the formula NHR₆ R₇, or especially a corresponding ammoniumsalt thereof, into compounds of formula I wherein X is a radical--C(═NH)--NR₆ R₇.

Compounds of formula I wherein X is an N-hydroxyamidino radical--C(═NR₈)--NHOH can be converted, for example by reaction with ironpentacarbonyl [Fe(CO)₅ ], into other compounds of formula I wherein X isan analogous amidino radical --C(═NR₈)--NH₂ (see, for example, J. Chem.Soc. Chore. Commun. 1975, 761).

Free compounds of formula I obtainable in accordance with the processhaving salt-forming properties can be converted into their salts in amanner known per se; compounds having basic properties can be convertedinto their salts, for example, by treatment with acids or suitablederivatives thereof, and compounds having acidic properties can beconverted into their salts, for example, by treatment with bases orsuitable derivatives thereof.

Especially, free compounds of formula I that have salt-formingproperties and that are obtainable in accordance with the process can beconverted in a manner known per se into their salts: for example,compounds having basic properties can be converted by treatment withacids, either with the protic acids [PA] themselves or preferably withother protic acids, for example organic acids that do not fall withinthe definition of [PA], such as formic acid, acetic acid andmethanesulfonic acid, or inorganic acids, such as sulfuric acid,hydrohalic acids, such as HF, HCl, HBr or HI, also hydrazoic acid orphosphoric acid. Hydrohalic acids are especially preferred. The reactiontakes place analogously for the preparation of acid addition salts ofbases of formula I with acids [PA].

The acid addition salts of bases of formula I, especially those withprotic acids other than [PA], can also be converted into the freecompounds. That can be effected, for example, by conversion into thefree base, for example by reaction of the salt of a compound of formulaI used as starting material with a hydroxy base, such as an alkali metalhydroxide, for example NaOH or KOH, in aqueous solution in the presenceor, preferably, absence of an organic solvent, as defined mentionedabove, also by dialysis, using ion exchangers or by gel chromatogaphy.

As a result of the close relationship between the compounds of formula Iin free form and in the form of salts, hereinabove and hereinbelow anyreference to the free compounds or their salts is to be understood asincluding the corresponding salts or free compounds, respectively, asappropriate and expedient.

Owing to the close relationship between the compounds of formulae II,III, IV and also V, VI and VII in free form and, insofar as thementioned compounds contain salt-forming groups, in the form of salts,hereinbefore and hereinafter the free compounds and their salts are alsoto be understood as being the corresponding salts, for example acidaddition salts or also salts with bases, and the free compounds,respectively, where appropriate and where the context so allows.

The preparation of salts, for example of the compounds of formulae II,III and IV having salt-forming groups, is carried out analogously to thepreparation of salts of the compounds of formula I (Process c) below).

The compounds, including their salts, can also be obtained in the formof hydrates, or their crystals may include, for example, the solventused for crystallisation.

Mixtures of isomers obtainable in accordance with the invention can beseparated into the individual isomers in a manner known per se;racemates can be separated, for example, by the formation of salts withoptically pure salt-forming reagents and separation of thediastereoisomeric mixture so obtainable, for example by fractionalcrystallisation.

The above-mentioned reactions can be carried out under reactionconditions known per se, in the absence or, usually, in the presence ofsolvents or diluents, preferably those solvents or diluents which areinert towards the reagents used and are solvents therefor, in theabsence or presence of catalysts, condensation agents or neutralisingagents, and, depending upon the nature of the reaction and/or thereactants, at reduced, normal or elevated temperature, for example in atemperature range of from approximately -70° C. to approximately 190°C., preferably from approximately -20° C. to approximately 150° C., forexample at the boiling point of the solvent used, especially in thereaction mixture concerned, or at room temperature, under atmosphericpressure or in a closed vessel, where appropriate under pressure, and/orin an inert atmosphere, for example under a nitrogen atmosphere.

The protic acids [PA] are known, can be prepared in accordance withprocesses known per se or are commercially available.

In the process of the present invention it is preferable to use thosestarting materials which result in the compounds described at thebeginning as being especially valuable.

In the process of the present invention, it is preferable to use thosestarting materials that lead to the acid addition salts described at thebeginning as being especially valuable.

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage of the process is usedas starting material and the remaining process steps are carried out, orin which a starting material is formed under the reaction conditions oris used in the form of a derivative, for example a salt thereof.

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage of the process is usedas starting material and the remaining process steps are carried out, orin which a starting material is formed under the reaction conditions oris used in the form of a derivative, for example a salt, thereof.

Pharmaceutical Compositions

The present invention relates also to pharmaceutical compositions thatcomprise one of the pharmacologically active compounds of formula I orespecially one of the pharmacologically active acid addition salts of abase of formula I with an acid [PA] as active ingredient. Compositionsfor enteral, especially oral, and for parenteral administration areespecially preferred. The compositions comprise the active ingredient onits own or, preferably, together with a pharmaceutically acceptablecarrier. The dosage of the active ingredient depends upon the disease tobe treated and upon the species, its age, weight and individualcondition, and also upon the mode of administration.

The pharmaceutical compositions comprise from approximately 0.1% toapproximately 95% active ingredient, dosage forms in single dose formpreferably comprising from approximately 1% to approximately 90% activeingredient and dosage forms that are not in single dose form preferablycomprising from approximately 0.1% to approximately 20% activeingredient. Unit dose forms, such as dragees, tablets or capsules,comprise from approximately 1 mg to approximately 500 mg of activeingredient.

The pharmaceutical compositions of this invention are prepared in amanner known per se, for example by means of conventional mixing,granulating, confectioning, dissolving or lyophilising processes. Forexample, pharmaceutical compositions for oral use can be obtained bycombining the active ingredient with one or more solid careers,optionally granulating a resulting mixture, and, if desired, processingthe mixture or granules, if necessary with the addition of additionalexcipients, to form tablets or dragee cores.

Suitable careers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tri-calcium phosphate or calciumhydrogen phosphate, also binders, such as starches, for example corn,wheat, rice or potato starch, methylcellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and/or, if desired, disintegrators, such as theabove-mentioned starches, also carboxymethyl starch, cross-linkedpolyvinylpyrrolidone, alginic acid or a salt thereof, such as sodiumalginate.

Additional excipients are especially flow conditioners and lubricants,for example silicic acid, talc, stearic acid or salts thereof, such asmagnesium or calcium stearate, and/or polyethylene glycol, orderivatives thereof.

Dragee cores can be provided with suitable, optionally enteric.coatings, there being used inter alia concentrated sugar solutions whichmay contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycoland/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures, or, for the production of entericcoatings, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Colourings or pigments may be added to the tablets or dragee coatings,for example for identification purposes or to indicate different dosesof active ingredient.

Orally administrable pharmaceutical compositions also include dry-filledcapsules consisting of gelatin, and also soft, sealed capsulesconsisting of gelatin and a plasticiser, such as glycerol or sorbitol.The dry-filled capsules may contain the active ingredient in the form ofgranules, for example in admixture with fillers, such as corn starch,binders and/or glidants, such as talc or magnesium stearate, andoptionally stabilisers. In soft capsules, the active ingredient ispreferably dissolved or suspended in suitable liquid excipients, such asfatty oils, paraffin oil or liquid polyethylene glycols, to whichstabilisers may also be added.

Other oral dosage forms are, for example, syrups prepared in customarymanner which comprise the active ingredient, for example, in suspendedform and in a concentration of about 0.1% to 10%, preferably about 1%,or in a similar concentration that provides a suitable single dose, forexample, when administered in measures of 5 or 10 ml. Also suitable are,for example, powdered or liquid concentrates for the preparation ofshakes, for example in milk. Such concentrates may also be packaged insingle dose quantities.

Suitable rectally administrable pharmaceutical compositions are, forexample, suppositories that consist of a combination of the activeingredient and a suppository base. Suitable suppository, bases are, forexample, natural or synthetic triglycerides, paraffin hydrocarbons,polyethylene glycols or higher alkanols.

For parentoral administration there are especially suitable aqueoussolutions of an active ingredient in water-soluble form, for example inthe form of a water-soluble salt, or aqueous injection suspensions thatcontain viscosity-increasing substances, for example sodiumcarboxymethylcellulose, sorbitol and/or dextran, and, if desired,stabilisers. The active inorient, optionally together with excipients,can also be in the form of a lyophilisate and can be made into asolution prior to parenteral administration by the addition of suitablesolvents.

An isotonic solution for infusion can be prepared especially by theaddition of suitable salts, such as NaCl, buffers, such as phosphatebuffers, for example with sodium as counter-ion, and/or sugar alcohols,such as mannitol, it being optionally possible for others of thementioned excipients also to be present.

Solutions such as are used, for example, for parenteral administrationcan also be used as infusion solutions.

The invention relates also to a method of treating the above-mentionedpathological conditions. The compounds of this invention can beadministered prophylactically or therapeutically, preferably in the formof pharmaceutical compositions. In the case of an individual having abody weight of about 70 kg the daily dose administered is fromapproximately 1 mg to approximately 1000 mg, preferably approximatelyfrom 25 to 100 mg in the case of oral administration and approximatelyfrom 2 to 50 mg in the case of parenteral administration, of a compoundof the present invention.

The invention relates also to a method of treating the above-mentioneddiseased states, caused especially by a lack of S-adenosylmethioninedecarboxylase-inhibition, which respond to treatment with an inhibitorof S-adenosylmethionine decarboxylase. The acid addition salts of thepresent invention, especially of bases of formula I and an acid [PA],may be administered prophylactically or therapeutically, especially inamounts that are suitable for inhibiting S-adenosylmethioninedecarboxylase, and they are used preferably in the form ofpharmaceutical compositions. In the case of a body weight ofapproximately 70 kg, a daily dose, especially one that is effectiveagainst the mentioned diseases, of from approximately 1 mg toapproximately 1000 mg, preferably approximately from 25 to 100 mg in thecase of oral administration or approximately from 2 to 50 mg in the caseof parenteral administration, of an acid addition salt of the presentinvention is administered, for example to a warm-blooded animal, such asa human, that is in need of such treatment because it is suffering froma protozoa infection or from tumours.

The invention relates also to a pharmaceutical composition that issuitable for administration to a mammal, for example a human, for theprevention or treatment of a disease that responds to treatment with aninhibitor of S-adenosylmethionine decarboxylase, especially a tumourdisease or a protozoa infection, which composition comprises an mount ofan acid addition salt of formula I, or tautomers thereof, of the presentinvention, especially of bases of formula I and an acid [PA], that iseffective in the inhibition of S-adenosylmethionine decarboxylase, and apharmaceutically acceptable carrier.

The following Examples illustrate the present invention; temperaturesare given in degees Celsius. The following abbreviations are used:abs.=absolute (anhydrous); D₂ O=deuterised watchDMF=N,N-dimethylformamide; DMSO-d₆ =perdeuterised dimethyl sulfoxide:ether=diethyl ether; ethyl acetate=acetic acid ethyl ester; IR=infraredspectroscopy; m.p.=melting point: THF=tetrahydrofuran; MS (FAB)=massspectrum ("Fast Atom Bombardment")

EXAMPLE 1 4-Amidino-1-indanone-2'-amidinohydrazone dihydrochloride

A solution of 3.8 g (27.9 mmol) of aminoguanidine hydrogen carbonate in200 ml of water and 14.7 ml of 2N hydrochloric acid is heated to 60°and, with stirring, a solution of 5.85 g (27.8 mmol) of4-amidino-1-indanone hydrochloride in 200 ml of methanol is addedthereto within a period of 30 minutes. The reaction mixture is boiled atreflux for 24 hours and, after cooling, concentrated to dryness byevaporation. The residue is suspended in 50 ml of ethanol, filtered,washed with ethanol and ether and dried, yielding the title compoundcontaining 1 mol of water of crystallisation, m.p. >330°; MS(FAB):(M+H)⁺ =231; ¹ H--NMR (D₂ O): δ=8.08 (d, 1H; 7.75 (d, 1H); 7.58 (t, 1H;3.35 (m,2H); 2.96 (m,2H).

The starting compounds are prepared as follows:

(a) 4-Thiocarbamoyl-1-indanone

A solution of 12.1 g (77 mmol) of4-cyano-1-indanone [Coll. Czechoslov.Chem. Commun. 43, 3227 (1978)] in 220 ml of pyridine and 10.6 ml (77mmol) of triethylamine is saturated with hydrogen sulfide for 3 hours at40° and then stirred for a further 16 hours at the same temperature.After cooling, the reaction mixture is concentrated to dryness byevaporation and then 300 ml of water are added to the residue. Theyellow product that crystallises out is filtered off with suction,washed with water, dried and recrystallised from ethyl acetate, yieldingstarting compound (a), m.p. 197° (decomp.).

b) 4-Amidino-1-indanone hydrochloride

10.8 g (54 mmol) of triethyloxonium tetrafluoroborate are added at roomtemperature under argon to a solution of 9.8 g (51.3 mmol) of4-thiocarbamoyl-1-indanone in 500 ml of absolute methylene chloride.After 16 hours a mixture of 4.2 g of potassium carbonate and 4.2 ml ofwater is added to the reaction solution. The mixture is then stirredbriefly and filtered, and the filtrate is washed with water. The organicphase is dried over magnesium sulfate, filtered and concentrated byevaporation. The resulting crude ethylthioimino ether is dissolved in160 ml of absolute ethanol: 3.3 g (60 mmol) of ammonium chloride areadded and the mixture is heated at reflux for 20 hours. After cooling,the reaction mixture is concentrated to dryness by evaporation. Startingcompound (b) is purified by chromatogaphy on 1000 ml of Amberlite®ER-180 resin (water as eluant) and recrystallised from ethanol/ether,m.p. 215°-218° (decomp.).

EXAMPLE 2 4-Amidino-1-indanone-2'-(N-hydroxyamidino)-hydrazonedihydrochloride

A solution of 394 mg (1.5 mmol) of1-amino-3-hydroxyguanidine-4-toluenesulfonate in 6 ml of water and 0.75ml (1.5 mmol) of 2N hydrochloric acid is added to a solution of 316 mg(1.5 mmol) of 4-amidino-1-indanone hydrochloride (Example 1b) in 7 ml ofmethanol, and the mixture is heated at reflux for 2 hours and stirred atroom temperature for 16 hours. The reaction mixture is concentrated byevaporation and the residue is purified by chromatography (Pharmaciacolumn SR-28-100) on silica gel OPTI-UP C₁₂ (water as eluant, 5 mlfractions, throughflow rate 27.5 ml/h). The contents of fractions 58-78are combined and concentrated by evaporation, and the residue iscrystallise from ethanol, yielding the title compound in the form ofwax-like crystals, MS (FAB): (M+H)⁺ =247; ¹ H--NMR (D₂ O): δ=8.06 (d,1H; 7.73 (d, 1H; 7.58 (t, 1H; 3.36 (m,2H); 2.98 (m,2H).

EXAMPLE 3 5-Amidino-1-tetralone-2'-amidinohydrazone dihydrochloride

0.675 g (3 mmol) of 5-amidino-1-tetralone hydrochloride is added to asolution of 0.41 g (3 mmol) of aminoguanidine hydrogen carbonate in 31.5ml of 0.1N hydrochloric acid and the mixture is heated at reflux for 72hours. After cooling, the mixture is concentrated to dryness byevaporation and the title compound is recrystallised from methanolether,m.p. 250°; MS (FAB): (M+H)⁺ =245; ¹ H--NMR (DMSO-d6): δ=113 (s, 1H); 9.5(m,4H); 8.65 (d, 1H); 7.92 (m,3H); 7.52 (d, 1H); 7.46 (t, 1H); 2.7-2.85(m,4H); 1.9 (m,4H).

The stating compounds are prepared as follows:

(a) 5-Cyano-1-tetralone

0.41 g (4.5 mmol) of copper(I) cyanide is added to a solution of 1.0 g(4.4 mmol) of 5-bromo-1-tetralone [J. Org. Chem. 49, 4226 (1984)] in 1.3ml of DMF and stirred for 6 hours at 160°. The reaction mixture is thencooled to 80° and a solution of 1.6 g of iron(III) chloride hexahydratein 2.5 ml of water and 0.44 ml of concentrated hydrochloric acid isadded. The reaction mixture is stirred for 45 minutes, cooled, dilutedwith water and extracted with toluene. The organic phase is washed withwater, dried over magnesium sulfate, filtered and concentrated byevaporation, yielding starting compound (a) in the form ofyellowish-orange crystals. IR (CH₂ Cl₂): 2220, 1690 cm⁻¹ ; ¹ H--NMR(CDCl₃): δ=8.26 (q, 1H; 7.81 (q, 1H; 7.43 (t, 1H; 3.21 (t,2H): 2.72(t,2H); 2.23 (m,2H).

(b) 5-Thiocarbamoyl-1-tetralone

Analogously to Example 1a, 10.6 g (62 mmol) of 5-cyano-1-tetralone in200 ml of pyridine and 8.6 ml of methylmine are treated with hydrogensulfide and worked up, yielding starting compound (b) in the form ofyellow crystals, m.p. 200°-205°.

(c) 5-Amidino-1-tetralone hydrochloride

Analogously to Example 1b, 8.6 g (42 mmol) of5-thiocarbamoyl-1-terralone are treated with 8.8 g (44 mmol) oftriethyloxonium tetrafluoroborate and 2.6 g (49 mmol) of ammoniumchloride, yielding starting compound (c) in the form of slightly pinkcrystals, MS (FAB): (M+H)⁺ =189.

EXAMPLE 4 4-Thiocarbamoyl-1-indanone-2'-amidinohydrazone hydrochloride

1.36 g (10 mmol) of aminoguanidine hydrogen carbonate and 10 ml of 2Nhydrochloric acid are added to a solution of 1.9 g (10 mmol) of4-thiocarbamoyl-1-indanone (Example 1a) in 50 ml of ethanol and themixture is heated at reflux for 24 hours. After cooling, the reactionmixture is concentrated to dryness by evaporation, yielding the titlecompound.

EXAMPLE 5 4-Amidino-1-indanone-2'-amidinohydrazone dihydrochloride

Analogously to Example 1b,4-thiocarbamoyl-1-indanone-2'-amidinohydrazone hydrochloride (Example 4)is reacted with triethyloxonium tetrafluoroborate and ammonium chloride,yielding the title compound, m.p. >330°; MS (FAB): (M+H)⁺ =231; ¹ H--NMR(D₂ O): δ=8.08 (d, 1H; 7.75 (d, 1H; 7.58 (t, 1H; 3.35 (m,2H); 2.96(m,2H).

EXAMPLE 6 4-Amidino-1-indanone-2'-amidinohydrazone dihydrochloride

1.2 ml of a 1N sodium methoxide solution in methanol are added to asolution of 0.26 g (1 mmol) of 4-cyano-1-indanone-2'-amidinohydrazonehydrochloride in 5 ml of absolute methanol and the mixture is heated atreflux for 16 hours. After cooling, 0.16 g (3 mmol) of solid ammoniumchloride is added to the reaction mixture which is then stirred for 1hour at 60°. The reaction mixture is then concentrated by evaporationand the residue is crystallised from dilute ethanol, yielding the tidecompound, m.p. >330°.

The starting compound is prepared as follows:

(a) 4-Cyano-1-indanone-2'-amidinohydrazone hydrochloride Analogously toExample 1,314 mg (2 mmol) of 4-cyano-1-indanone are dissolved in 20 mlof methanol; a solution of 272 mg (2 mmol) of aminoguanidine hydrogencarbonate in 9 ml of water and 1 ml of 2N hydrochloric acid is added andthe mixture is stirred at reflux for 4 days. After cooling, the reactionmixture is concentrated to dryness by evaporation and the residue iscrystallised from water, yielding stamping compound (a), m.p. >230°: ¹H--NMR (DMSO-d₆ /D₂ O): δ=8.16 (d, 1H; 7.9 (d, 1H; 7.55 (t, 1H; 3.28(m,2H); 2.9 (m,2H); IR(Nujol): 2190 cm⁻¹ (CN).

EXAMPLE 7 4-(N-Hydroxyamidino)-1-indanone-2'-amidinohydrazonedihydrochloride

0.2 g (3 mmol) of hydroxylamine hydrochloride are suspended in 1 ml ofabsolute ethanol, and 2 ml of a 1N sodium ethoxide solution in ethanolare added. This mixture is stirred for 1 hour and filtered. A solutionof 0.26 g (1 mmol) of 4-cyano-1-indanone-2'-amidinohydrazonehydrochloride (Example 6a) in 2 ml of water is added to the filtrate,and the mixture is heated at reflux for 6 hours. After cooling, thereaction mixture is concentrated by evaporation and the title compoundis crystallised from water, m.p. >250°; ¹ H--NMR (DMSO-d₆ +D₂ O): δ=8.12(m,1H; 7.55 (m,2H); 3.22 (m,2H); 2.83 (m,2H).

EXAMPLE 8 4-Amidino-2-methyl-1-indanone-2'-amidinohydrazonedihydrochloride

Analogously to Example 1, the title compound is prepared from4-cyano-2-methyl-1-indanone (see U.S. Pat. No. 3,956,363).

EXAMPLE 9 5-Amidino-6-methoxy-1-tetralone-2'-amidinohydrazonedihydrochloride

Analogously to Example 1, the title compound is prepared from5-cyano-6-methoxy-1-tefralone [Chem. Pharm. Bull. 31, 2329 (1983)].

EXAMPLE 10 4-Amidino-6-methyl-1-indanone-2'-amidinohydrazonedihydrochloride

Analogously to Example 3, the title compound is prepared from4-bromo-6-methyl-1-indanone (Bull. Soc. Chim. France 1964, 3103),m.p. >250° C.; MS (FAB): (M+H)⁺ =245; ¹ H--NMR CD₂ O): δ=7.89 (s, 1H);7.62 (s, 1H); 3.34 (t, 2H); 2.96 (t, 2H); 2.45 (s, 3H).

EXAMPLE 11 4-Amidino-6-methoxy-7-methyl-1-indanone-2'-amidinohydrazonedihydrochloride

Analogously to Example 3, the title compound is prepared from4-bromo-6-methoxy-7-methyl-1-indanone (J. Chem. Soc. Perkin Trans. 11974, 1911).

EXAMPLE 12 4-Amidino-6,7-dimethyl-1-indanone-2'-amidinohydrazonedihydrochloride

Analogously to Example 3, the title compound is prepared from4-bromo-6,7-dimethyl-1-indanone [J. Het. Chem. 24, 677 (1987)].

EXAMPLE 13 4-Amidino-7-hydroxy-3-methyl-1-indanone-2'amidinohydrazonedihydrochloride

Analogously to Example 3, the title compound is prepared from4-bromo-7-hydroxy-3-methyl-1-indanone [Indian J. Chem. Sect. B 24B, 1061(1985)].

EXAMPLE 14 4-(Methylamidino)-1-indanone-2'-amidinohydrazonedihydrochloride

Analogously to Example 1b, 4-thiocarbamoyl-1-indanone-2'-aminohydrazonehydrochloride (Example 4) is reacted with triethyloxoniumtetrafluoroborate and methylammonium chloride, yielding the titlecompound.

EXAMPLE 15 4-Amidino-1-indanone-2'-amidinohydrazone dihydrochloride

9.45 g (44.9 mmol) of 4-amidino-1-indanone hydrochloride (see Example1b) are added to a solution of 6.12 g (45 mmol) of aminoguanidinehydrogen carbonate in 100 ml of water and 46 ml of 1N hydrochloric acidand the mixture is stirred for 24 hours at 24°. The product thatcrystallises out is filtered off with suction, washed with a smallamount of water and recrystallised from 300 ml of water, yielding thetitle compound containing 1 mol of water of crystallisation, m.p. >330°;MS (FAB): (M+H)⁺ =231; ¹ H--NMR (D₂ O): δ=8.08 (d, 1H; 7.75 (d, 1H; 7.58(t, 1H; 3.35 (m,2H); 2.96 (m,2H).

EXAMPLE 16 4-Amidino-2-methyl-1-indanone-2'-amidinohydrazonedihydrochloride

A solution of 1.0 g (5.0 mmol) of 4-amidino-2-methyl-lindanonehydrochloride and 0.68 g (5.0 mmol) of aminoguanidine hydrogen carbonatein 10 ml of 0.5N hydrochloric acid is stirred for 120 hours at 25°. Theproduct that crystallises out is filtered off with suction, washed witha small amount of water and dried, yielding the title compound,m.p. >250°; MS (FAB): (M+H)⁺ =245; ¹ H--NMR (D₂ O): δ=7.95 (d, 1H: 7.66(d, 1H; 7.48 (t, 1H; 3.45 (m,2H); 2.85 (d, 1H: 1.12 (d,3H).

The starting compounds are prepared as follows:

(a) 4-Thiocarbamoyl-2-methyl-1-indanone

Analogously to Example 1a, 11.1 g (65 mmol) of4-cyano-2-methyl-1-indanone [see U.S. Pat. No. 3,956,363] in 200 ml ofpyridine and 9.7 ml of triethylamine are treated with hydrogen sulfideand worked up, yielding starting compound (a) in the form of yellowcrystals, m.p. 195°-198° (decomp.); ¹ H--NMR (DMSO-d₆): δ=9.6I (s,1H);7.71 (m2H); 7.48 (m,1H; 3.48 (m,1H: 2.81 (m.2H); 1.23 (s,3H); 1.19(s,3H).

(b) 4-Amidino-2-methyl-1-indanone hydrochloride

Analogously to Example 1b, 10.2 g (50 mmol) of starting compound (a) aretreated with 11.0 g (55 mmol) of triethyloxonium tetrafluoroborate and3.2 g (60 mmol) of ammonium chloride, yielding starting compound (b) inthe form of pink crystals. It is immediately reacted further.

EXAMPLE 17 4-Amidino-6,7-dimethyl-1-indanone-2'-amidinohydrazonedihydrochloride

Analogously to Example 1, the title compound is prepared from4-amidino-6,7-dimethyl-1-indanone hydrochloride, m.p. >240° C.: MS(FAB): (M+H).sup.⊕ =259; ¹ H--NMR (D₂ O): δ=7.43 (s, 1H; 3.12 (m,2H);2.75 (m,2H); 2.43 (s,3H); 2.24 (s,3H).

The starting compounds are prepared as follows:

(a) 4-Cyano-6,7-dimethyl-1-indanone

A mixture of 17.8 g (74.5 mmol) of 4-bromo-6,7-dimethyl-1-indanone [J.Het. Chem. 24, 677 (1987)] and 7.3 g (82 mmol) of copper(I) cyanide in18 ml of DMF is stirred for 6 hours at 170°. The reaction mixture isthen cooled to 100° and 200 ml of toluene and a solution of 31.2 g ofiron(III) chloride hexahydrate in 47 ml of water and 8.2 ml ofconcentrated hydrochloric acid are added in succession thereto. Thereaction mixture is stirred for 20 minutes at 70°, cooled and dilutedwith toluene and water. The organic phase is separated off, washed withwater, a semi-saturated sodium hydrogen carbonate solution and againwith water, dried and concentrated by evaporation. The residue iscrystallised from ethyl acetate and ether and corresponds to startingcompound (a). Beige crystals having a melting point of 160°-163° areobtained; IR (CH₂ Cl₂): 2220, 1710 cm⁻¹.

(b) 4-Thiocarbamoyl-6,7-dimethyl-1-indanone

Analogously to Example 1 a, 10 g (54.1 mmol) of starting compound (a) in200 ml of pyridine and 7.5 ml of methylamine are treated with hydrogensulfide and worked up, yielding starting compound (b) in the form ofyellow crystals, m.p. 207°-208°; ¹ H--NMR (DMSO-d₆): δ=10.03 (s, 1H;9.49 (s,1H; 7.49 (s,1H); 3.12 (m.2H); 2.61 (m,2H); 2.54 (s,3H); 2.29(s,3H).

(c) 4-Amidino-6,7-dimethyl-1-indanone hydrochloride

Analogously to Example 1b, 4.4 g (20 mmol) of starting compound (b) aretreated with 4.26 g (21 mmol) of triethyloxonium tetrafluoroborate and1.2 g (24 mmol) of ammonium chloride, yielding starting compound (c) inthe form of beige crystals.

EXAMPLE 18 4-Amidino-6,7-dimethoxy-1-indanone-2'-amidinohydrazonedihydrochloride

0.73 g (2.7 mmol) of 4-amidino-6,7-dimethoxy-1-indanone hydrochloride isadded to a solution of 0.4 g (3 mmol) of aminoguanidine hydrogencarbonate in 6 ml of 0.5N hydrochloric acid and the mixture is stirredfor 24 hours at 50°. After cooling, the product that has crystallisedout is filtered with suction, washed with a small amount of water anddried, yielding the title compound, m.p. >220°; MS (FAB): (M+H)⁺ =291; ¹H--NMR (D₂ O): δ=7.45 (s, 1H; 3.97 (s,6H); 3.27 (m,2H); 2.98 (m,2H).

The starting compounds are prepared as follows:

(a) 4-Cyano-6,7-dimethoxy-1-indanone

A mixture of 6.57 g (24.2 mmol) of 4-bromo-6,7-dimethoxy-1-indanone[Can. J. Chem. 57, 1603 (1979)] and 2.5 g (28 mmol) of copper(I) cyanidein 7 ml of DMF is stirred for 5.75 hours at 170°. The reaction mixtureis then cooled to 100° and then 70 ml of toluene and a solution of 9.7 g(36 mmol) of iron(III) chloride hexahydrate in 15.6 ml of water and 3.5ml of concentrated hydrochloric acid are added in succession thereto.The reaction mixture is then stirred for 30 minutes at 80°, cooled anddiluted with toluene and water. The organic phase is separated off,washed with water, a semi-saturated sodium hydrogen carbonate solutionand again with water, dried and concentrated by evaporation. The residueis distilled at 150°-160°/0.1 mbar in a bulb tube still and correspondsto starting compound (a), m.p. 150°; IR (CH₂ Cl₂): 2220, 1710 cm⁻¹ ;1H--NMR (CDCl₃): δ=7.33 (s, 1H; 4.12 (s,3H); 3.90 (s,3H); 3.19 (m,2H);2.76 (m,2H).

(b) 4-Thiocarbamoyl-6,7-dimethoxy-1-indanone

Analogously to Example 1a, 3.7 g (17 mmol) of starting compound (a) in100 ml of pyridine and 2.4 ml of triethylamine are treated with hydrogensulfide and worked up, yielding starting compound (b) in the form ofbright yellow crystals, m.p. 196°-199°; ¹ H--NMR (DMSO-d₆): δ=10.06(s,1H); 9.50 (s,1H); 7.41 (s,1H; 3.84 (s,6H); 3.13 (m,2H); 2.63 (m.2H).

(c) 4-Amidino-6,7-dimethoxy-1-indanone hydrochloride

Analogously to Example 1b, 3.3 g (13 mmol) of starting compound (b) aretreated with 2.8 g (14 mmol) of triethyloxonium tetrafluoroborate and0.8 g (15 mmol) of ammonium chloride, yielding starting compound (c) inthe form of beige crystals, m.p. 188° (with decomp.); ¹ H--NMR(DMSO-d₆):δ=9.4 (s,3H); 7.63 (s,1H); 3.92 (s,3H); 3.89 (s,3H); 3.18 (m,2H); 2.68(m,2H).

EXAMPLE 19 4-Amidino-3-methyl-1-indanone-2'-amidinohydrazonedihydrochloride

300 mg (2.3 mmol) of aminoguanidine hydrogen carbonate in 4 ml of 0.5Nhydrochloric acid are added to a solution of 300 mg(1.3 mmol) of4-amidino-3-methyl-1-indanone hydrochloride in 6 ml of water and themixture is stirred for 24 hours at 80°. The reaction mixture is cooledand concentrated by evaporation and the residue is purified bychromatogaphy on 180 ml of Amberlite® ER-180 resin with water as eluant.The title compound is recrystallised from methanol/ether, m.p. >250°;R_(f) =0.18 (silica gel, methylene chloride/methanol/conc. ammonia5:3:1); MS (FAB): (M+H)⁺ =245; ¹ H--NMR (D₂ O): δ=7.97 (d, 1H; 7.64(d,1H; 7.49 (t, 1H; 3.86 (m, 1H); 3.17 (q, 1H; 2.49 (d, 1H; 1.24 (d,3H).

The starting compounds are prepared as follows:

(a) 4-Cyano-3-methyl-1-indanone

A mixture of 2.6 g (11.5 mmol) of 4-bromo-3-methyl-1-indanone [J. Org.Chem. 22, 1019 (1957)] and 1.14 g (12.7 mmol) of copper(I) cyanide in2.5 ml of DMF is stirred for 6 hours at 170°. The reaction mixture isthen cooled to 100°, and 50 ml of toluene and a solution of 4.5 g (16.5mmol) of iron(III) chloride hexahydrate in 7 ml of water and 1.7 ml ofconcentrated hydrochloric acid are added in succession thereto. Thereaction mixture is stirred for 20 minutes at 70°, cooled and dilutedwith toluene and water. The organic phase is separated off, washed withwater, a semi-saturated sodium hydrogen carbonate solution and againwith water, dried and concentrated by evaporation. The residue isdistilled at 100°-120°/0.05 mbar in a bulb tube still and corresponds tostarting compound (a), m.p. 109°-111°; IR (CH₂ Cl₂): 2220, 1710 cm⁻¹ ;1H--NMR (CDCl₃): δ=7.92 (m,2H); 7.52 (t, 1H; 3.73 (m,1H: 3.03 (q,1H):2.40 (q, 1H; 1.55 (d,3H).

(b) 4-Thiocarbamoyl-3-methyl-1-indanone

Analogously to Example 1a, 1.45 g (8.47 mmol) of starting compound (a)in 25 ml of pyridine and 1.2 ml of triethylamine are treated withhydrogen sulfide and worked up, yielding starting compound (b) in theform of pale yellow crystals, m.p. 198°-200°; ¹ H--NMR (DMSO-d₆): δ=9.78(s,1H; 7.65 (m,2H); 7.46 (m,1H); 3.98 (m, 1H; 2.95 (q,1H; 2.26 (q, 1H;1.25 (d,3H).

(c) 4-Amidino-3-methyl-1-indanone hydrochloride

Analogously to Example 1b, 0.96 g (4.68 mmol) of starting compound (b)is treated with 1.0 g (4.93 mmol) of triethyloxoniurn tetrafluoroborateand 0.3 g (6 mmol) of ammonium chloride, yielding starting compound (c)in the form of beige crystals, 1H--NMR (DMSO-d₆): δ=9.59 (s,4H); 7.65(m,2H); 7.46 (m, 1H; 3.98 (m,1H; 2.95 (q,1H; 2.26 (q,1H; 1.25 (d,3H).

EXAMPLE 20 4-Amidino-1-indanone-2'-amidinohydrazone dihydrochloride

A mixture of 0.32 g (1 mmol) of 4-(N-hydroxyamidino)-1-indanone2'-amidinohydrazone dihydrochloride (Example 7), 0.36 ml (2 mmol) oftriethylamine and 0.2 g (1 mmol) of iron pentacarbonyl in 10 ml ofabsolute THF is boiled at reflux for 16 hours. The reaction mixture isthen concentrated by evaporation and the residue is crystallised fromdilute hydrochloric acid, yielding the title compound, m.p. >330°.

EXAMPLE 21 4-Amidino-2-ethyl-1-indanone-2'-amidinohydrazonedihydrochloride

3-(2-Bromophenyl)-2-ethylpropionic acid (German Patent 2 733 868) iscyclised with polyphosphoric acid at elevated temperature to form thecorresponding 1-indanone and converted into the title compoundanalogously to Example 3. M.p. >250° C.; MS (FAB): (M+H)⁺ =259; ¹ H--NMR(D₂ O): δ=7.96 (d, 1H; 7.65 (d, 1H; 7.48 (t, 1H; 2.95-3.48 (m,3H);1.3-1.8 (m,2H); 0.83 (t,3H).

EXAMPLE 22 4-Amidino-2-n-butyl-1-indanone-2'-amidinohydrazonedihydrochloride

3-(2-Bromophenyl)-2-n-butylpropionic acid (German Patent 2 733 868) iscyclised with polyphosphoric acid at elevated temperature to form thecorresponding 1-indanone and converted into the title compoundanalogously to Example 3.

EXAMPLES 23

Capsules containing 0.25 g of active ingredient. for example one of thecompounds of Examples 1 to 22, can be prepared as follows:

    ______________________________________                                        Composition (for 5000 capsules)                                               ______________________________________                                        active ingredient        1250   g                                             talc                     180    g                                             wheat starch             120    g                                             magnesium stearate       80     g                                             lactose                  20     g                                             ______________________________________                                    

The pulverulent substances are forced through a sieve of 0.6 mm meshsize and mixed together. 0.33 g portions of the mixture are introducedinto gelatin capsules using a capsule-filling machine.

EXAMPLE 24

10,000 tablets are prepared, each tablet comprising 5 mg of activeingredient, for example one of the compounds prepared according toExamples 1 to 22:

    ______________________________________                                        Composition                                                                   ______________________________________                                        active ingredient     50.00   g                                               lactose               2535.00 g                                               corn starch           125.00  g                                               polyethylene glycol 6000                                                                            150.00  g                                               magnesium stearate    40.00   g                                               purified water    quantum satis                                               ______________________________________                                    

Procedure

All the pulverulent constituents are passed through a sieve of 0.6 mmmesh size. Then the active ingredient, the lactose, the magnesiumstearate and half of the starch are mixed together in a suitable mixer.The other half of the starch is suspended in 65 ml of water and theresulting suspension is added to a boiling solution of the polyethyleneglycol in 260 ml of water. The resulting paste is added to the powdermixture and granulated, if necessary, with the addition of more water.The granules are dried overnight at 35° C., forced through a sieve of1.2 mm mesh size and compressed to form tablets having a breaking notch.

EXAMPLE 25 4-Amidino-2-propylindanone-1-amidinohydrazone dihydrochlonde

Analogously to Example 21, the title compound is prepared stoning from2-bromobenzyl bromide and malonic acid diethyl ester, m.p. >250° C.; MS(FAB): (M+H)⁺ =273; ¹ H--NMR (D₂ O): δ=7.98 (d, 1H; 7.67 (m,1H): 7.49(t, 1H); 3.44 (m,2H); 3.01 (m, 1H; 1.1-1.75 (m,4H): 0.81 (t,3H).

The following Examples of acid addition salts of bases of formula I withacids [PA] also serve to illustrate the invention but do not limit thescope thereof in any way.

Temperatures are given in deuces Celsius (°C.). If no temperature isindicated, the reaction concerned is carried out at room temperature. Ifconcentration by evaporation is carried out, a rotary evaporator is usedunless otherwise indicated.

The values for proton nuclear magnetic resonance spectroscopy are givenin ppm ("parts per million") based on tetramethylsilane (δ=0) as theinternal standard. d=doublet, s=singlet, t=triplet, m=multipict.

In the case of elemental analyses, the empirical formula, the molecularweight, and calculated and found analysis values are indicated.

The shortened forms and abbreviations used have the following meanings:

    ______________________________________                                        anal.    elemental analysis                                                   calc.    calculated                                                           D.sub.2 O                                                                              dideuterium oxide                                                    DMSO-d.sub.6                                                                           completely deuterised dimethyl sulfoxide                             .sup.1 H-NMR                                                                           proton nuclear magnetic resonance spectroscopy                       m.p.     melting point                                                        decomp.  with decomposition                                                   ______________________________________                                    

EXAMPLE 26 4-Amidino-1-indanone-2'-amidinohydrazone dicyclamate

A solution of 717 mg (4 mmol) of N-cyclohexylsulfamic acid in 20 ml ofmethanol is added to a solution of 460 mg (2 mmol) of4-amidinoindanone-1-amidinohydrazone in 80 ml of methanol and the batchis concentrated to dryness by evaporation. The residue is dissolved inethanol and crystallised by the addition of diethyl ether to yield thetitle compound, m.p. 210° (decomp.); ¹ H--NMR (D₂ O): δ 7.97 (d, 1H;7.64 (d, 1H: 7.47 (t, 1H; 3.25 (m,2H): 2.9 (m,4H); 1-2 (m,20H); anal.for C₂₃ H₄₀ N₈ O₆ S₂ (588.75): Calc. 46.92% C, 6.85% H, 19.03% N. found46.5% C. 6.9% H, 19.0% N.

The starting material is prepared as follows:

a) 4-Amidino-1-indanone-2'-amidinohydrazone

9.63 g (30 mmol) of 4-amidino-1-indanone-2'-amidinohydrazonedihydrochloride (prepared in accordance with one of the processesdescribed in Examples 1, 5.6, 15 or 20, for example in accordance withExample 1)) are dissolved in 900 ml of distilled water heated to 70°-80°C. and cooled to 10° C. 30 ml of 2N sodium hydroxide solution are addeddropwise to the resulting solution with stirring. The product whichseparates out is filtered off with suction, washed with a small amountof ice-water and dried to yield the title compound, m.p. 250° (decomp.).

EXAMPLE 27 4-Amidino-1-indanone-2'-amidinohydrazone dioctanoate

631 μl (4 mmol) of octanoic acid are added to a solution of 460 mg (2mmol) of 4-amidino-1-indanone-2'-amidinohydrazone (Example 26a)) in 80ml of methanol and the batch is concentrated to dryness by evaporation.The residue is dissolved in ethanol and crystallised by the addition ofdiethyl ether to yield the title compound, m.p. 1 (decomp.); ¹ H--NMR(DMSO-d₆): δ 8.03 (d, 1H; 7.52 (d, 1H; 7.47 (t, 1H; 3.19 (m,2H); 2.85(m,2H); 1.98 (t,4H); 1.42 (m,4H); 1.19 (s,24H); 0.81 (t,6H); anal. forC₂₇ H₄₆ N₆ O₄ (518.70): calc. 62.52% C, 8.94% H. 16.20% N, found 62.3%C, 8.9% H, 16.2% N.

EXAMPLE 28 4-Amidino-1-indanone-2'-amidinohydrazone disalicylate

A solution of 830 mg (6 mmol) of salicylic acid in 50 ml of ethanol isadded to a solution of 690 mg (3 mmol) of4-amidino-lindanone-2'-amidinohydrazone (Example 26a)) in 100 ml ofmethanol and the reaction mixture is concentrated to half the volume byevaporation. 70 ml of water are added to the solution, whereupon thetitle compound crystallises out, m.p. 206°-9° (decomp.); anal. for C₂₅H₂₆ N₆ O₆ (507.1): calc. 59.13% C, 5.19% H, 16.55% N, found 59.3% C,5.2% H, 16.8% N.

EXAMPLE 29 4-Amidino-1-indanone-2'-amidinohydrazone dibenzenesulfonate

A solution of 975 mg (6 mmol) of benzenesulfonic acid in 50 ml ofmethanol is added to a solution of 690 m g (3 mmol) of4-amidino-1-indanone-2'-amidinohydrazone (Example 26a)) in 100 ml ofmethanol and the batch is concentrated to dryness by evaporation. Theresidue is crystallised from ethanol to yield the title compound,m.p. >250° (decomp.); ¹ H--NMR (D₂ O): δ 7.38-7.95 (m,16H); 3.21 (m,2H);2.78 (m,2H); anal. for C₂₃ H₂₆ N₆ O₆ S₂ (546.63): calc. 50.54% C, 4.79%H. 15.37% N, found 50.4% C, 4.8% H, 15.6% N.

EXAMPLE 30

further salts

EXAMPLE 30a 4-Amidinoindanone-1-amidinohydrazone succinate

A solution of 472 mg (4 mmol) of succinic acid in 120 ml of methanol isadded to a solution of 920 mg (4 mmol) of4-amidino-1-indanone-2'-amidinohydrazone in 120 ml of methanol. Theproduct which crystallises out is filtered off with suction, washed witha small amount of methanol and dried to yield the title compound, m.p.200° (decomp.); anal. for C₁₅ H₂₀ N₆ O₄.1.04 H₂ O (367.10): calc. 49.08%C, 6.06% H. 22.89% N, found 49.13% C, 6.07% H, 23.04% N.

EXAMPLE 30b 4-Amidinoindanone-1-amidinohydrazone adipate

A solution of 146 mg (1 mmol) of adipic acid in 25 ml of ethanol isadded to a solution of 230 mg(1 mmol) of4-amidino-1-indanone-2'-amidinohydrazone in 30 ml of methanol. Theproduct which crystallises out is filtered off with suction, washed witha small amount of ethanol and dried to yield the title compound, m.p.200° (decomp.); anal. for C₁₇ H₂₄ N₆ O₄.0.25 H₂ O (380.92): cate. 53.60%C, 6.48% H, 22.06% N. found 53.79% C, 6,73% H, 21.93% N.

EXAMPLE 30c 4-Amidinoindanone-1-amidinohydrazone-1,5-naphthalenedisulfonate

A solution of 1.49 g (4 mmol) of 1,5-naphthalene disulfonic acid in 100ml of methanol is added to a solution of 920 mg (4 mmol) of4-amidino-1-indanone-2'-amidinohydrazone in 120 ml of methanol. Theproduct which crystallises out is filtered off with suction, washed witha small amount of methanol and dried to yield the tide compound.m.p. >250°: anal. for C₂₁ H₂₂ N₆ O₆ S₂.2.36 H₂ O (561.09): calc. 44.95%C, 4.80% H, 14.98% N, found 45.06% C, 4.98% H, 15.21% N.

EXAMPLE 30d 4-Amidinoindanone-1-amidinohydrazone ethane disulfonate

Analogously to any one of the Examples 26 to 30c) given hereinbefore,4-amidino-1-indanone-2'-amidinohydrazone is converted into the titlecompound using 1,2-ethane-disulfonic acid.

EXAMPLE 30e 4-Amidinoindanone-1-amidinohydrazone L-tartrate

A solution of 600 mg (4 mmol) of L-(+)-tartaric acid in 100 ml ofmethanol is added to a solution of 920 mg (4 mmol) of4-amidino-1-indanone-2'-amidinohydrazone in 120 ml of methanol. Theproduct which crystallises out is filtered off with suction, washed witha small amount of methanol and dried to vield the title compound, m.p.190° (decomp.); anal. for C₁₅ H₂₀ N₆ O₆.0.26 H₂ O (385.04): calc. 46,79%C, 5.37% H. 21.83% N, found 46.83% C, 5.43% H, 21.87% N.

EXAMPLE 30f 4-Amidinoindanone-1-amidinohydrazone citrate

A solution of 210 mg (1 mmol) of citric acid in 10 ml of methanol isadded to a solution of 230 mg (1 mmol) of4-amidino-1-indanone-2'-amidinohydrazone in 30 ml of methanol. Theproduct which crystallises out is filtered off with suction, washed witha small amount of methanol and dried to yield the titlecompound,,m.p. >220° (decomp.): anal. for C₁₇ H₂₂ N₆ O₇ (422.40): calc.48.34% C, 5.25% H, 19.90% N, found 48.23% C, 5.33% H, 20.07% N.

EXAMPLE 30g 4-Amidinoindanone-1-amidinohydrazone dilactate

Analogously to any one of the Examples given hereinbefore andhereinafter, 4-amidino-1-indanone-2'-amidinohydrazone is converted intothe title compound using lactic acid.

EXAMPLE 31

Analogously to any one of the above Examples 26 to 30g, the followingstarting compounds can be converted into the acid addition salts ofoctanoic acid, succinic acid, adipic acid, salicylic acid,cyclohexylsulfamic acid, ethanedisulfonic acid, benzenesulfonic acid,citric acid, tartaric acid and 1,5-naphthalenedisulfonic acid:

a) 4-amidino-1-indanone-2'-(N-hydroxyamidino)-hydrazone dihydrochloride(Example 2);

b) 5-Amidino-t-tetralone-2'-amidinohydrazone dihydrochloride (Example3);

c) 4-Thiocarbamoyl-1-indanone-2'-amidinohydrazone hydrochloride (Example4);

d) 4-(N-Hydroxyamidino)-1-indanone-2'-amidinohydrazone dihydrochloride(Example 7);

e) 4-Amidino-2-methyl-1-indanone-2'-amidinohydrazone dihydrochloride(Example 8);

f) 5-Amidino-6-methoxy-I-tetralone-2'-amidinohydrazone dihydrochloride(Example 9);

g) 4-Amidino-6-methoxy-7-methyl-1-indanone-2'-amidinohydrazonedihydrochloride (Example 11);

h) 4-Amidino-6,7-dimethyl-1-indanone-2'-amidinohydrazone dihydrochloride(Example 12);

i) 4-Amidino-7-hydroxy-3-methyl-1-indanone-2'-amidinohydrazonedihydrochloride (Example 13);

j) 4-(Methylamidino)-I-indanone-2'-amidinohydrazone dihydrochloride(Example 14);

k) 4-Amidino-6,7-dimethoxy-1-indanone-2'-amidinohydrazonedihydrochloride (Example 18);

l) 4-Amidino-6-methyl-1-indanone-2'-amidinohydrazone dihydrochloride(Example 10);

m) 4-Amidino-3-methyl-1-indanone-2'-amidinohydrazone dihydrochloride(Example 19);

n) 4-Amidino-2-ethyl-1-indanone-2'-amidinohydrazone dihydrochloride(Example 21);

o) 4-Amidino-2-n-butyl-1-indanone-2'-amidinohydrazone dihydrochloride(Example 22).

p) 4-Amidino-2-n-propyl-indanone-1-amidinohydrazone (Example Q).

EXAMPLE 32

Capsules, each containing 0.25 g of active ingredient, for example oneof the acid addition salts of Examples 26 to 31, can be prepared asfollows:

    ______________________________________                                        Composition (for 5000 capsules)                                               ______________________________________                                        active ingredient        1250   g                                             talc                     180    g                                             wheat starch             120    g                                             magnesium stearate       80     g                                             lactose                  20     g                                             ______________________________________                                    

The pulverulent substances are forced through a sieve having a mesh sizeof 0.6 mm and mixed. 0.33 g portions of the mixture are introduced intogelatin capsules by means of a capsule-filling machine.

EXAMPLE 33

10,000 tablets, each comprising 5 mg of active ingredient, for exampleone of the acid addition salts prepared in Examples 26 to 31, areprepared:

    ______________________________________                                        Composition:                                                                  ______________________________________                                        active ingredient     50.00   g                                               lactose               2535.00 g                                               corn starch           125.00  g                                               polyethylene glycol 6000                                                                            150.00  g                                               magnesium stearate    40.00   g                                               purified water    quantum satis                                               ______________________________________                                    

Method

All of the pulverulent constituents are passed through a sieve having amesh size of 0.6 min. The active ingredient, the lactose, the magnesiumstearate and half of the starch are then mixed in a suitable mixer. Theother half of the starch is suspended in 65 ml of water and theresulting suspension is added to a boiling solution of the polyethyleneglycol in 260 ml of water. The resulting paste is added to the powdermixture and granulated, where appropriate with the addition of morewater. The granules are dried overnight at 35° C., forced through asieve having a mesh size of 1.2 mm and compressed to form tablets havinga breaking notch.

What is claimed is:
 1. A process for the preparation of a compound offormula I: ##STR9## wherein A is a direct bond or --CH₂ --, X is aradical --C(═Y)--NR₆ R₇ ; Y is NH; Z is NH; R₁ is hydrogen or one or twosubstituents from the group consisting of lower alkyl, hydroxy, loweralkoxy and halogen; R₂ is hydrogen or lower alkyl; the radicals R₃,R₄and R₆ are hydrogen; and R₅ and R₇ are each independently of the otherhydrogen, lower alkyl or hydroxy; a tautomer thereof, or apharmaceutically acceptable salt thereof, which process comprises(a)condensing a compound of formula II ##STR10## wherein the group CW₁ W₂is carbonyl, functionally modified carbonyl or protected carbonyl and A,X, R₁ and R₂ are as defined for formula I, or a salt thereof, ifsalt-forming groups are present, with an amine of formula III ##STR11##wherein Z, R₃, R₄ and R₅ are as defined for formula I, or a saltthereof, or (b) in a compound of formula IV ##STR12## wherein W₃ is aradical that can be converted into a group X in formula I and A, Z, R₁,R₂, R₃, R₄ and R₅ are as defined for formula I, or a salt thereof,converting the radical W₃ into the group X; and, if desired, convertinga resulting compound of formula I into a different compound of formula Iand/or, if desired, converting a resulting salt into the free compoundor into a different salt and/or, if desired, converting a resulting freecompound of formula I having salt-forming properties into a salt.
 2. Theprocess according to claim 1 for the preparation of a compound offormula I with the name 4-amidino-1-indanone-2'-amidinohydrazone, or apharmaceutically acceptable salt thereof.